The vasculature in Alzheimer'a[euro][TM]s disease: a new therapeutic target for an old disease?

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Author: Paula Grammas
Date: Sept. 2011
From: Therapy(Vol. 8, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Editorial
Length: 2,032 words
Lexile Measure: 1350L

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Author(s): Paula Grammas 1



Alzheimer'âs disease; amyloid; antioxidants; cerebrovasculature; cognitive decline; inflammation; neurodegeneration; neuropathology; neurotoxicity; oxidative stress

Alzheimer'âs disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. AD is an irreversible neurodegenerative disease that affects more than 5.3 million people in the USA and is projected to sharply increase to 8 million by 2030 [101] . Every 69 s, someone in America develops AD, and it is the sixth leading cause of death. In 2011, the cost of caring for those with AD to American society will total an estimated US$183 billion. Unless something is done, the costs of AD in 2050 will total $1.1 trillion [101] . While deaths from other major diseases, including heart disease and stroke, have significantly decreased in recent years, deaths from AD increased by 66% between 2000 and 2008 [101] . More than a decade has passed since the first US FDA-approved drugs for the 'treatment'â of AD were unveiled. Yet, despite intense research efforts, there are currently no disease-modifying drugs that can affect the relentless progression of this devastating disease. New thinking on disease pathogenesis and novel therapeutic approaches are urgently needed.

Currently, there are two classes of drugs that are FDA approved and prescribed for the treatment of AD: acetylcholinesterase inhibitors and N -methyl-D-aspartic acid (NMDA) receptor antagonists. Cholinesterase inhibitors inhibit the activity of the primary enzyme (acetylcholinesterase) that degrades acetylcholine, thus preserving levels of this neurotransmitter, which can slow the decline in cognitive function and improve overall well-being in AD patients. Four cholinesterase inhibitors are currently approved by the FDA for the treatment of AD: tacrine, donepezil, rivastigmine and galantamine. Memantine, the fifth FDA-approved drug, is an NMDA receptor antagonist. Excitotoxic stimulation of NMDA receptors by glutamate is thought to contribute to neuronal injury in AD. Double-blinded, randomized, placebo-controlled trials have shown the significant benefit in cognitive function, language and activities of daily living when combinations of memantine and donepezil have been used [1] . However, these drug regimens, while improving clinical symptoms and quality of life for limited time periods, do not affect progression of the disease or prevent underlying neuronal injury and death.

Central to designing effective therapies is an understanding of the underlying pathologic processes that drive disease progression. Unfortunately, the causal factor(s) that trigger and/or drive this disease remain to be defined. The amyloid cascade hypothesis, which postulates that amyloid-[beta]β (A[beta]β) is the primary neurotoxic species involved in disease pathogenesis, has dominated research in the AD field for the past 20 years [2,3] . Indeed, therapeutic approaches aimed at disrupting the amyloid cascade, including γγ-secretase inhibitors for reducing A[beta]β formation, agents for preventing aggregation of amyloid oligomers, and immunotherapy for enhancing clearance of amyloid, have been exhaustively pursued [1,4,5] . However, A[beta]β-centered therapeutic trials have not produced the beneficial clinical results anticipated [3,4] . A[beta]β-lowering agents such as R-fluribiporfin have shown promise in Phase II trials but failed in Phase III [6] . Several other anti-A[beta]β agents have also failed in Phase III trials. The failure of these trials, as well...

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Gale Document Number: GALE|A268609827